g100
play

G100 P OT E N T I N N AT E I M M U N E A C T I VATO R LECTURE: - PowerPoint PPT Presentation

Mar 21, 2024 •111 likes •308 views

G100 P OT E N T I N N AT E I M M U N E A C T I VATO R LECTURE: G100 + Pembrolizumab (Dr. Carlos Paya) CONFERENCE: New Drugs in Hematology Conference (Oct 2018) Forward-looking Statements This presentation contains forward-looking

  1. G100 P OT E N T I N N AT E I M M U N E A C T I VATO R LECTURE: G100 + Pembrolizumab (Dr. Carlos Paya) CONFERENCE: New Drugs in Hematology Conference (Oct 2018)

  2. Forward-looking Statements This presentation contains forward-looking statements with respect to, among other things, our business, financial condition, strategy and prospects, and has been prepared solely for informational purposes. All statements, other than statements of historical fact, regarding our strategy, potential future products, prospects, plans, opportunities and objectives constitute “forward - looking statements.” These statements are not guarantees of future performance and involve a number of unknown risks, assumptions, uncertainties and factors that are beyond our control. Given these risks, assumptions and uncertainties, you should not place undue reliance on these forward- looking statements. Important factors that could cause actual results to differ materially from those indicated by such forward-looking statements include, among others, our history of net losses and expected net losses for the foreseeable future, that we have no product candidates approved for commercialization and may never achieve profitability, that we will require additional capital to finance our operations, that we may not be able to successfully develop, obtain regulatory approval and commercialize our product candidates, all of which are novel and in early clinical development, and those other risks that will be set forth under the header “Risk Factors,” “Note Regarding Forward - Looking Statements” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in our periodic reports filed with the Securities and Exchange Commission, including our Quarterly Report for the period ended June 30, 2018. All statements contained in this presentation are made only as of the date of this presentation and are subject to uncertainty and changes. Except as required by law, we expressly disclaim any responsibility to update such forward-looking statements, whether as a result of new information, future events or otherwise. 2

  3. TLR4 Signaling: 3 Independent Pathways Resiquimod LPS, G100 CPG Poly-IC:LC LPS, G100 2 2 1 1 3 ? Receptor Caspase-11 Caspase-1 IL-1 β IL-18 Bacterial infection Viral infection 3 Modified from: Zhao, Front Immunol 2013 and Desbien et al., Eur J Immunol. (2014)

  4. Powerful + Safe Activator of TME Innate Immunity • GLA is the first small molecule from IMDZ’s TLR4 agonist platform • GLA is formulated for efficacy: • The squalene emulsion formulation (GLA-SE) provides a depo effect and allows for intracytoplasmic internalization; this compound is named G100 . • An aqueous formulation (GLA-AF) only binds the extracellular receptor • API manufacturing uses chemical synthesis with strong IP • >1000 pts exposed as a vaccine adjuvant G100: GLA at the Core and > 100 pts as an intratumoral agent with (Glucopyranosyl lipid A) no Grade ≥3 SAEs 4

  5. G100 Acts Locally to Drive Systemic Benefit 1. Targets TLR4 in any accessible 1 2 tumor via • TME Dendritic cells leading to enhance antigen presentation and cytokine and chemokine production, and overall inflammation • Malignant B cells become exposed to incoming T and NK cells. (XRT) 2. Attracts and expands pre- existing T and NK cells 3. Effective in combo w/ other 3 agents (e.g. ACT, IMiDs, checkpoint inhibitors, others) 4. Designed for local tumor control + systemic immunity to control distant, non- treated tumors (abscopal effect) (XRT) 5

  6. G100 Induces Proinflammatory Cytokine/Chemokine Milieu I N C R E A S E D C D 8 T I L S I N F L PAT I E N T S Chemokines All Genes T cell function Cytotoxicity panCancer 106006TP: pre-G100 tumor biopsy 106006TO: post-G100 tumor biopsy Immune Profiling During G100 Treatment TCR sequencing indicates clonal expansion of TILs in tumor post-G100 Infiltration of CD8 (Green) and macrophage (Yellow) co-localize with Disrupted Tumor Cells (CD20, Cyan Blue) CD20+ cells dispursed CD8+, PD-1+, PD-L1+ high T o p 2 5 T IL T C R c lo n e s 0 .3 F re q u e n c y (% ) 0 .2 0 .1 0 .0 p r e -T x T IL p o s t-T x T IL Green: CD8; Yellow: CD68; Cyan Blue: CD20; Red: PD-L1; Magenta: PD-1 6

  7. G100 D E V E LO P M E N T I N F O L L I C U L A R LY M P H O M A : F I R S T P I VOTA L PAT H

  8. G100 Clinical Benefit in Follicular Lymphoma I NI T I AL PAT H I N UNMET NEED POPUL AT ION • Earlier trial design and goal: inject G100 into radiated lesion and observe distal, non-treated lesions to confirm systemic effect from local injection - achieved • Activity shown in relapsed/refractory & naïve patients: moving forward in patients with three prior therapies (unmet need 1 ), with strategy to expand to earlier lines • Potential to be the first chemotherapy-free, immunotherapy regimen in FL Monotherapy Ph 1 Dose Escalation 20ug Dose Expansion G100 5, 10, 20ug + XRT (n=9) G100 20ug + XRT (n=14) ASCO 2017 Targeting Fall Medical Congress 2 Combination Therapy Ph 2 Randomized (10ug) Upcoming Pivotal Ph 2 G100 + XRT (n=13) G100 + Pembrolizumab 3 G100 + XRT + pembrolizumab (n=13) • FDA concurs on single-arm trial with ORR/DOR ASH 2017 & Q1’18 Update endpoints • Adaptive design will refine final study; intended to support a BLA 4 1 Per interactions with FDA 2 Presentations subject to acceptance. 3 Regimen not finalized – under discussion 8 with FDA. 4 Dependent on study design agreement with FDA, as well as data

  9. G100 +/- Pembrolizumab Phase 2 PAT I ENT CHARAC T ERI ST I CS G100 (n=13) G100 + P (n=13) Age: median (range) 64 (39-72) 58 (36-80) Gender , M/F 10M/3F 10M/3F ECOG, 0 / 1 10 / 3 11 / 2 Grade 1 / 2 11 (85%) 10 (77%) 3 2 (15%) 2 (15%) Unknown/Missing 1 (8%) Stage At IIA/B 1 0 Entry IIIA/B 6 8 IVA/B 5 5 Unknown/Missing 1 0 Prior Naïve 6 (46%) 8 (62%) Treatment R / R 7 (54%) 5 (38%) #Tx: 1-2 2 (15%) 2 (15%) >3 5 (39%) 3 (23%) Median (Range) 3 (1 to 5) 4 (1 to 6) Prior Auto-SCT 3 2 Growing Tumor at Entry 6 (46%) 8 (62%) 9

  10. G100 +/- Pembrolizumab Phase 2 SAF ET Y • Overall, the majority of AEs reported were Grade 1 or 2 for both treatment arms and the number of events were similar in both treatment groups Patients with at least 1 TEAE G100 (n=13) G100 + P (n=13) All 9 (69%) 11 (85%) Grade 1 6 (46%) 6 (46%) Grade 2 3 (23%) 4 (31%) Grade 3 1 (8%) 1 0 Grade 4 0 0 Grade 5 0 0 SAE 0 1 (8%) 1 1 There was 1 SAE and grade 3 event that occurred in a single patient on the G100+P arm which was considered related to pembrolizumab and not G100 10

  11. G100 +/- Pembrolizumab Phase 2 EF F I CACY • Combination w/ pembro is synergistic (pembro monotherapy 11% ORR; similar to other αPD -1s) 1 • Data initially presented at ASH 2017, updated in March 2018 G100 (n=13) G100 + P (n=13) Best Objective Response Rate (all lesions) 2 ORR (PR, pts (%) (-50% to 100%) 2 (15%) 7 (54%) Treatment naïve [PR, pts (%)] 0/6 (0%) 3/8 (38%) Relapsed/Refractory [PR, pts (%)] 2/7 (29%) 4/5 (80%) PD, pts (%) 2 (15%) 1 (8%) Abscopal Tumor Reduction (Min 10% - non-injected distal lesions) Overall, pts (%) 7 (54%) 10 (77%) Range of shrinkage, % 22% - 79% 10% - 89% Shrinkage ≥10cm 2 , pts (%) 3 (23%) 5 (39%) 1 Pembrolizumab and cemiplimab showed 11% and 9% ORR, respectively, at ASH 2017; nivolumab showed 40% ORR in 10 patients, which the company views as a relative outlier. 2 Responses are best responses in all index lesions combined (injected and non injected) with or without follow-up confirmation based on irRC (Wolchok, et al., 2009). Data cut off: 28Feb2018 11

  12. G100 +/- Pembrolizumab Phase 2 CONCORDANCE B ET WEEN AL L AND AB SCOPAL L ESI ONS G100 (n= 13) G100 + P (n= 13) All lesions Abscopal lesions Total Best % Change from Baseline of Sum of Product Diameters (SPD) * Abscopal Best % Change from Baseline of SPD 12 *Single baseline abscopal lesion was 4.5x3 cm

  13. Ph2 G100 +/- Pembrolizumab EF F I CACY I N COMB I NAT I ON PAT I ENTS • ORR progressive over time (n=13) 13

  14. Ph2 G100 +/- Pembrolizumab PROGRESSI ON F REE SURV I VAL (PFS) G100 + P (n=13) G100 (n=13) Individual Patients Individual Patients mPFS = 7.4 mos mPFS = 11.1 mos Progression Free Survival (Months)  Denotes patient has not progressed Data cutoff Feb 28, 2018 14

  15. Biomarker: Analysis of CD8 + TILs • Addition of Pembro (P) demonstrated a trend to increased CD8 + TILs • Association observed between increased TILs and clinical responses • TIL increase appears to be dose dependent, evaluation of G at 20 µg ongoing; rationale for higher doses and combination with P G100 ( n= 10) G100 + P ( n= 11) N= 10 N= 11 * * * CD8 + Cells/mm 2 * * * * * * * * PR pt SD pt (including MR) with abscopal shrinkage *R/R (previously treated) patient Immune Infiltrate Responders Non-Responders Odds Ratio p-value CD8 (ratio of post/pre) 1.61 0.9 30 0.032 CD8/CD4 (ratio of post/pre) 2.99 1.14 5.1 0.054 CD8/Foxp3 (ratio of post/pre) 3.16 0.88 34 0.06 IHC analysis of pre and post tumors from patients in the Phase 1 dose escalation and this randomized phase 2 (n=36) 15

Recommend

More recommend